Antiretroviral therapy (ART) has lessened but not eliminated the central nervous system (CNS) impact of human immunodeficiency virus (HIV). With effects on cognition and brain integrity now subtler, yet chronic with unknown long-term implications, the potential of comorbid conditions to moderate, obscure or ameliorate HIV effects is increasingly important. Young adults (?youth?) have high rates of both new HIV infection and understudied common comorbidities with significant potential to influence HIV?s CNS presentation: cannabis use and cumulative adversity. Both may alter immune functioning and inflammation as pathways for their influence on HIV?s CNS effects, in addition to their independent impact. Our preliminary data show that worse cognitive and neuroimaging outcomes in youth with HIV (YWH) compared to controls (e.g., worse memory and executive functioning, thinner prefrontal cortex, altered functional activation using magnetoencephalography [MEG]) are attenuated or, in some cases, reversed by light to moderate, but not heavy, cannabis use. We hypothesize that worse cognitive and neuroimaging outcomes in treated YWH, compared to controls, in the context of no cannabis use will be ameliorated by mild to moderate cannabis use, while high cannabis use frequency will be associated with worse outcomes in both groups. Of importance, fully understanding the interplay of HIV and cannabis may require consideration of lifetime experiences of adversity. Strong evidence shows that exposure to adverse circumstances, such as maltreatment, violence, and stress, can alter immune and CNS systems, and such exposure is common among YWH and comparable seronegative risk groups. We will assess the influence of cumulative adversity in mediating effects of cannabis and HIV. The proposed study will determine the interactive effects of HIV, cannabis and cumulative adversity on CNS structure and function in 75 YWH (age 18-24) and 75 comparable controls. We will use innovative neuroimaging approaches (MEG to measure functional activity and advanced diffusion approaches), along with brain structure and metabolism and neurocognitive assessment. We will examine mediation of HIV, cannabis and cumulative adversity interactions by inflammation and immune activation, assessed using plasma biomarkers. Examining the interplay of these influences on CNS function and structure will be facilitated by careful characterization of substance use, assessment of cumulative adversity burden rather than single traumatic events, and advanced statistical techniques. Thus, we will examine interactive HIV and cannabis effects on key brain systems; model underlying mechanisms; and examine an important yet understudied influence, cumulative adversity. The study has potential for high impact by improving detection of HIV?s CNS effects and our understanding of pathogenesis. It would enable better prevention of CNS decline, institution of CNS-targeted treatments and cure strategies, and in general mitigation of the CNS impact of HIV for individuals who are early in infection and still in the midst of neurodevelopment where early detection may have the greatest benefit.